It has recently been determined that HIV protease inhibiting compounds are useful for inhibiting HIV protease in vitro and in vivo and are also useful for inhibiting an HIV (human immunodeficiency virus) infection.
It has also recently been determined that compounds of the formula I: ##STR1## wherein R.sub.1 is lower alkyl and R.sub.2 and R.sub.3 are phenyl are particularly useful as inhibitors of HIV-1 and HIV-2 protease and are useful for inhibiting HIV protease in vitro and in vivo and are also useful to inhibit HIV infections.
In particular, the compound of formula II, has been found to be especially effective as an inhibitor of HIV-1 and HIV-2 protease. ##STR2##
The most preferred compounds of formula II are (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)-L-valinyl)amino)-2-(N-( (5-thiazolyl)methoxycarbonyl)amino)- 1,6-diphenyl-3-hydroxyhexane (compound III) or an acid addition salt thereof and (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)-D-valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino )-1,6-diphenyl-3-hydroxyhexane (compound IV) or an acid addition salt thereof.
The preparation of compound III and its use as an inhibitor of HIV protease are disclosed in PCT Patent Application No. WO94/14436, published Jul. 7, 1994, which is incorporated herein by reference. The method disclosed for preparing compound III is shown in Scheme I. This method involves an amide bond forming coupling reaction of intermediates 1 and 2 in the presence of 1-hydroxybenzotriazole and diimide such as dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC) and the like. Such a process is not suitable for manufacturing scale production of III or IV because the diimides are toxic, they are sensitizers and they present a variety of other handling and workup problems.
An alternative process is shown in Scheme II. In this process, intermediate 1 is converted to a mixed anhydride (wherein R* is loweralkyl, for example, by reaction with an alkyl chloroformate such as isobutylchloroformate and the like or by reaction with an alkanoyl chloride such as pivaloylchloride and the like). The mixed anhydride is then reacted (without isolation) with intermediate 2. Because of the high reactivity of the intermediate mixed anhydride, this process often leads to unacceptable amounts of undesired side products.
Therefore, there is a continuing need for an improved coupling process for the preparation of III and IV. ##STR3##